This invention relates to a process for purifying and isolating 2,4,5-trifluorobenzoic acid from a solvent such as N-methylpyrrolidone. In particular, it relates to a method in which soluble 2,4,5-trifluorobenzoic acid is converted into an insoluble salt then back into the acid again.
2,4,5-Trifluorobenzoic acid (2,4,5--TiFBA) is used as an intermediate in preparing quinolone antibacterials. It is prepared by a process that begins with tetrachlorophthalic anhydride. Tetrachlorophthalic anhydride is first hydrodechlorinated in NaOH/Zn to produce 3,4,6-trichlorophthalic acid, followed by imidization using methylamine to form 3,4,6-trichloro-N-methylphthalimide. That product is fluorinated by KF to form 3,4,6-trifluoro-N-methyl phthalimide, which is hydrolyzed to produce 3,4,6-trifluorophthalic acid. Decarboxylation results in a solution of 2,4,5-TiFBA in an organic decarboxylating solvent such as N-methylpyrrolidone (NMP).
The solution also contains an isomer of the acid, 2,3,5-trifluorobenzoic acid (2,3,5-TiFBA), as well as other contaminants. The removal of the 2,3,5-TiFBA can be accomplished by recrystallization, but the yield is low. Morever, it is very difficult to separate the 2,4,5-TiFBA from NMP by distillation because they appear to form an azeotrope. NMP also has a very strong affinity for TiFBA and clean-up of even a trace amount of NMP contamination requires high vacuum (&lt;1 mm Hg) drying or chromatography. Moreover, if the solution is heated for too long it darkens and the TiFBA product decomposes, which is unacceptable for a highly pure substance to be used in making drugs. Even if the NMP is removed, the product very often must still undergo recrystallizations to remove the 2,3,5- isomer and other contaminants. All these involve lengthy steps and are not suitable for industrial applications. An article by Neil J. O'Reilly et al. in Synlett Letters, October 1990, pp. 609-610, titled "An Expedient Route To The Quinolone Antibacterial Intermediate, 2,4,5-Trifluorobenzoic Acid," describes a purification method which involves vacuum desiccation and chromatography, but that method requires stringent process conditions and equipment and is not suitable for mass production in industry.